The past several years have witnessed ongoing improvements in the prognosis of individuals with advanced HIV-1 disease. The improvements have been due, in part, to the advent of nucleoside analog reverse transcriptase inhibitors and to advances in the management of the opportunistic infectious and neoplastic complications of HIV-1 infection. With the increasing emphasis on the earlier initiation of antiretroviral chemotherapy, the ongoing development of antiretroviral agents with novel mechanisms of action, and the additive or synergistic benefits from combination antiretroviral chemotherapy, it is likely that further advances in the management of HIV-1 infection will evolve over the next several years. Despite these advances, there are likely to be limits t other benefits that might be expected form antiretroviral chemotherapy with traditional small molecule approaches. Each of the currently available nucleoside analog reverse transcriptase inhibitors exhibits one or more dose limiting toxicities. Despite use of these agents, singly or in combination, disease progression is observed in virtually all patients over time. A number of factors may contribute to disease progression. These include the emergence of isolates of HIV-1 with reduced susceptibility to the antiretroviral agents employed, the incomplete inhibition of HIV-1 replication in vivo by currently available agents, and the inability of the host immune response to fully reconstitute itself after many years of ongoing immunologic depletion.